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- Title
Tumour-infiltrating neutrophils counteract anti-VEGF therapy in metastatic colorectal cancer.
- Authors
Schiffmann, Lars Mortimer; Fritsch, Melanie; Gebauer, Florian; Günther, Saskia Diana; Stair, Neil Richard; Seeger, Jens Michael; Thangarajah, Fabinshy; Dieplinger, Georg; Bludau, Marc; Alakus, Hakan; Göbel, Heike; Quaas, Alexander; Zander, Thomas; Hilberg, Frank; Bruns, Christiane Josephine; Kashkar, Hamid; Coutelle, Oliver
- Abstract
<bold>Background: </bold>Immune infiltration is implicated in the development of acquired resistance to anti-angiogenic cancer therapy. We therefore investigated the correlation between neutrophil infiltration in metastasis of colorectal cancer (CRC) patients and survival after treatment with bevacizumab. Our study identifies CD177+ tumour neutrophil infiltration as an adverse prognostic factor for bevacizumab treatment. We further demonstrate that a novel anti-VEGF/anti-Ang2 compound (BI-880) can overcome resistance to VEGF inhibition in experimental tumour models.<bold>Methods: </bold>A total of 85 metastatic CRC patients were stratified into cohorts that had either received chemotherapy alone (n = 39) or combined with bevacizumab (n = 46). Tumour CD177+ neutrophil infiltration was correlated to clinical outcome. The impact of neutrophil infiltration on anti-VEGF or anti-VEGF/anti-Ang2 therapy was studied in both xenograft and syngeneic tumour models by immunohistochemistry.<bold>Results: </bold>The survival of bevacizumab-treated CRC patients in the presence of CD177+ infiltrates was significantly reduced compared to patients harbouring CD177- metastases. BI-880 treatment reduced the development of hypoxia associated with bevacizumab treatment and improved vascular normalisation in xenografts. Furthermore, neutrophil depletion or BI-880 treatment restored treatment sensitivity in a syngeneic tumour model of anti-VEGF resistance.<bold>Conclusions: </bold>Our findings implicate CD177 as a biomarker for bevacizumab and suggest VEGF/Ang2 inhibition as a strategy to overcome neutrophil associated resistance to anti-angiogenic treatment.
- Publication
British Journal of Cancer, 2019, Vol 120, Issue 1, p69
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/s41416-018-0198-3